In addition to glucose, many other
carbohydrates ultimately enter the glycolytic pathway to
undergo energy-yielding degradation. The most significant
are the storage polysaccharides glycogen and starch, the
disaccharides maltose, lactose, trehalose, and sucrose,
and the monosaccharides fructose, mannose, and galactose.
We shall now consider the pathways by which these
carbohydrates can enter glycolysis.

Glycogen
and Starch Are Degraded by Phosphorolysis

The glucose units of the outer branches of glycogen
and starch gain entrance into the glycolytic pathway
through the sequential action of two enzymes: glycogen
phosphorylase (or the similar starch phosphorylase in
plants) and phosphoglucomutase. Glycogen phosphorylase
catalyzes the reaction in which an (α1→4) glycosidic
linkage joining two glucose residues in glycogen
undergoes attack by inorganic phosphate, removing the
terminal glucose residue as α-D--glucose-1-phosphate (Fig.
14-11). This phosphorolysis reaction that occurs during
intracellular mobilization of glycogen stores is
different from the hydrolysis of glycosidic bonds by
amylase during intestinal degradation of glycogen or
starch; in phosphorolysis, some of the energy of the
glycosidic bond is preserved in the formation of the
phosphate ester, glucose-1-phosphate.

Figure 14-10An industrial-scale fermentation. Microorganisms
are cultured in a sterilizable vessel containing
thousands of liters of growth medium made up of an
inexpensive carbon-and-energy source under carefully
controlled conditions, including low oxygen concentration
and constant temperature. After centrifugal separation of
the cells from the growth medium, the valuable products
of the fermentation are recovered from the cells or the
supernatant fluid.

Figure 14-11Removal
of a terminal glucose residue from the nonreducing end of
a glycogen chain by the action of glycogen phosphorylase.
This process is repetitive, removing successive glucose
residues until it reaches the fourth glucose unit from a
branch point (see Fig. 14-12). Amylopectin is degraded in
a similar fashion by starch phosphorylase.

Pyridoxal phosphate is an essential
cofactor in the glycogen phosphorylase reaction; its
phosphate group acts as a general acid catalyst,
promoting attack by Pi on the glycosidic bond. A quite
different role of pyridoxal phosphate as a cofactor in
amino acid metabolism will be described in detail in
Chapter 17.

Glycogen phosphorylase (or starch
phosphorylase) acts repetitively on the nonreducing ends
of glycogen (or amylopectin) branches until it reaches a
point four glucose residues away from an (α1→6) branch
point (see Fig. 11-15). Here the action of glycogen or
starch phosphorylase stops. Further degradation can occur
only after the action of a "debranching
enzyme," oligo (α1→6) to (α1→4)
glucantransferase, which catalyzes two
successive reactions that remove branches (Fig. 14-12).

Glucose-1-phosphate, the end product of the glycogen
and starch phosphorylase reactions, is converted into
glucose-6-phosphate by phosphoglucomutase,
which catalyzes the reversible reaction

Glucose-1-phosphate
glucose-6-phosphate

Phosphoglucomutase requires as a cofactor glucose-1,6-bisphosphate;
its role is analogous to that of 2,3-bisphosphoglycerate
in the reaction catalyzed by phosphoglycerate mutase
(Fig. 14-6). Phosphoglucomutase, like phosphoglycerate
mutase, cycles between a phosphorylated and
nonphosphorylated form. In phosphoglucomutase, however,
it is the hydroxyl group of a Ser residue in the active
site that is transiently phosphorylated in the catalytic
cycle.

Figure 14-12 Glycogen breakdown near (α1→6) branch
points. Following the sequential removal of terminal
glucose residues by glycogen phosphorylase (Fig. 14-11),
glucose residues near a branch are removed in a two-step
process that requires the action of a bifunctional
"debranching enzyme." First, the transferase
activity of this enzyme shifts a block of three glucose
residues from the branch to
a nearby nonreducing end, to which they are reattached in
(α1→4) linkage. Then the single glucose residue
remaining at the branch point, in (α1→6) linkage, is
released as free glucose by the enzyme's (α1→6)
glucosidase activity. The glucose residues are shown in
shorthand form, which omits the -H, -OH, and -CH2OH
groups from the pyranose rings.

In most organisms, hexoses other than glucose can
undergo glycolysis after conversion to a phosphorylated
derivative. D-Fructose, present in free form in many
fruits and formed by hydrolysis of sucrose in the small
intestine, can be phosphorylated by hexokinase, which
acts on a number of different hexoses:

Fructose + ATP

Mg2+

fructose-6-phosphate + ADP

In the muscles and kidney of vertebrates this is a
major pathway. In the liver, however, fructose gains
entry into glycolysis by a different pathway. The liver
enzyme fructokinase catalyzes the
phosphorylation of fructose, not at C-6, but at C-l:

Fructose + ATP

Mg2+

fructose-1-phosphate + ADP

The fructose-1-phosphate is then cleaved to form
glyceraldehyde and dihydroxyacetone phosphate by fructose-1-phosphate
aldolase.

Dihydroxyacetone phosphate is converted
into glyceraldehyde-3phosphate by the glycolytic enzyme
triose phosphate isomerase. Glyceraldehyde is
phosphorylated by ATP and triose kinase to
glyceraldehyde-3-phosphate:

Glyceraldehyde
+ ATP

Mg2+

glyceraldehyde-3-phosphate + ADP

Thus both products of fructose hydrolysis enter the
glycolytic pathway as glyceraldehyde- 3-phosphate.

D-Galactose, derived by hydrolysis of the disaccharide
lactose (milk sugar), is first phosphorylated at C-1 at
the expense of ATP by the enzyme galactokinase:

Galactose + ATP
galactose-1-phosphate + ADP

The galactose-1-phosphate is then converted into its
epimer at C-4, glucose-1-phosphate, by a set of reactions
in which uridine diphosphate (UDP) functions as a
coenzymelike carrier of hexose groups (Fig. 14-13).

There are several human genetic diseases in which
galactose metabolism is affected. In the most common form
of galactosemia, the enzyme UDP-glucose :
galactose-1-phosphate uridylyltransferase (Fig. 14-13) is
genetically defective, preventing the overall conversion
of galactose into glucose. Other forms of galactosemia
result when either galactokinase or
UDP-glucose-4-epimerase is genetically defective.

D-Mannose, which arises from the digestion of various
polysaccharides and glycoproteins present in foods, can
be phosphorylated at C-6 by hexokinase:

Mannose + ATP

Mg2+

mannose-6-phosphate + ADP

Mannose-6-phosphate is then isomerized by the action
of phosphomannose isomerase, to yield
fructose-6-phosphate, an intermediate of glycolysis.

Figure 14-13Pathway of the conversion of ngalactose into
n-glucose. The conversion proceeds through a
sugar-nucleotide derivative, UDP-galactose, which is
formed when galactose-1-phosphate displaces
glucose-1-phosphate from UDP-glucose. UDP-galactose is
then converted by UDP-glucose 4-epimerase to UDP-glucose.
The UDP-glucose is recycled through another round of the
same reaction. The net effect of this cycle is the
conversion of galactose-1-phosphate to
glucose-1-phosphate; there is no net production or
consumption of UDP-galactose or UDP-glucose.

Figure 14-14Lactase,
a disaccharidase of the intestinal epithelium, can be detected by
treating a thin section of intestinal tissue with an antibody
that specifically binds to the enzyme. The antibodies are made
visible in the electron microscope by attaching to them tiny
colloidal particles of gold, which appear as black
(electron-dense) dots in electron micrographs. (a)
Tissue from an adult who has retained high levels of lactase.
Microvilli are heavily labeled with antibodies that detect
lactase. (b) Intestinal microvilli in tissue
from an adult with lactose intolerance are much less heavily
labeled with antibodies against lactase.

Disaccharides cannot directly enter the glycolytic pathway;
indeed they cannot enter cells without first being hydrolyzed to
monosaccharides extracellularly. In vertebrates, ingested
disaccharides must first be hydrolyzed by enzymes attached to the
outer surface of the epithelial cells lining the small intestine
(Fig. 14-14), to yield their monosaccharide units:

Maltose + H2O

maltase

2 D-glucose

Lactose + H2O

lactase

D-galactose + D-glucose

Sucrose + H2O

sucrase

D-fructose + D-glucose

Trehalose + H2O

trehalase

2 D-glucose

The monosaccharides so formed are transported into the cells
lining the intestine, from which they pass into the blood and are
carried to the liver. There they are phosphorylated and funneled
into the glycolytic sequence as described above.

Lactose intolerance is a condition, common
among adults of most human races except Northern Europeans and
some Africans, in which the ingestion of milk or other foods
containing lactose leads to abdominal cramps and diarrhea.
Lactose intolerance is due to the disappearance after childhood
of most or all of the lactase activity of the intestinal cells
(Fig. 14-14b), so that lactose cannot be completely digested and
absorbed. Lactose not absorbed in the small intestine is
converted by bacteria in the large intestine into toxic products
that cause the symptoms of the condition. In those parts of the
world where lactose intolerance is prevalent, milk is simply not
used as a food by adults. Milk products digested with lactase are
commercially available in some countries as an alternative to
excluding milk products from the diet. In certain diseases of
humans, several or all of the intestinal disaccharidases are
missing because of genetic defects or dietary factors, resulting
in digestive disturbances triggered by disaccharides in the diet
(Fig. 14-14b). Altering the diet to reduce disaccharide content
sometimes alleviates the symptoms of these defects.